Submissions for variant NM_004168.4(SDHA):c.562C>T (p.Arg188Trp)

gnomAD frequency: 0.00001  dbSNP: rs553257776

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555353	SCV000651446	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 188 of the SDHA protein (p.Arg188Trp). This variant is present in population databases (rs553257776, gnomAD 0.004%). This missense change has been observed in individuals with gastrointestinal stromal tumor and/or paragangliomas (PMID: 23282968, 33362715; Invitae). ClinVar contains an entry for this variant (Variation ID: 472395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. Experimental studies have shown that this missense change affects SDHA function (PMID: 28724664). This variant disrupts the p.Arg188 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32741965; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000571189	SCV000674985	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The p.R188W variant (also known as c.562C>T), located in coding exon 5 of the SDHA gene, results from a C to T substitution at nucleotide position 562. The arginine at codon 188 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in individuals with a paraganglioma or gastrointestinal stromal tumor (Miettinen M et al, 2013 Feb;37:234-40; Ma X et al. Front Endocrinol (Lausanne), 2020 Dec;11:574662). Functional studies in yeast demonstrated that this variant impairs SDHA activity (Bannon AE et al. Clin Cancer Res, 2017 Nov;23:6733-6743). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003335474	SCV004043213	likely pathogenic	Paragangliomas 5	2023-09-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33362715, 23282968, 32741965, Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].